Antibodies with catalytic activity for a particular reaction can be elicited in the Balb/c mouse after immunization with an appropriate transition state analog. However, the inability to determine precisely the states of many reactions is a barrier to the general exploration of the novel phenomenon of antibody catalysis. A way around the general lack of precise structural information about the transition state might be found by pursuing the alternative approach of searching a large sample of the Balb/c repertoire for antibodies which can catalyze a particular reaction. This proposal seeks to demonstrate the versatility and power of a large hybridoma library which incorporates a significant fraction of the repertoire of specificities (not clonotypes) in the Balb/c mouse. The library, whose composition is substantially underway, is constructed by the PEG-assisted fusion of polyclonally activated B cell blasts from unimmunized Balb/c mice. The library will ultimately contain a large number (ca. 10.000) of discrete hybridoma populations, each of which is composed of at least 1 and usually 3 to 5 or more clones. This library will be screened to demonstrate that some of its members show catalytic activity. Chromogenic or radioactive substrates will be used to identify hybridoma populations that catalyze the hydrolysis of any one of a variety of structural motifs. In addition there is the possibility that among its members one can find a diverse spectrum of antibodies whose affinity or antigen specificity qualifies them as useful. The diversity of antigen reactivities represented in the library will be determined by screening its members against an antigen panel that includes differentiation antigens, different bacterial species, and solutions of soluble antigens (thyroxine, insulin, calmodulin, and digoxin) at submicromolar concentrations. The significance of this approach lies in its potential to provide an alternative route to the derivation of antibodies to immunization programs. Also, there is the intriguing possibility that antibodies whose expression is normally blocked by constraints of tolerance could be accessed by this technology. This might make it possible to derive antibodies to highly conserved determinants on particular types of molecules or specific categories of cells that are of interest in many different species.